Bis-triiodoisophthalamic acid compounds



United States Patent 3,541,141 BIS-TRIIODOISOPHTHALAMIC ACID COMPOUNDS of a noble metal catalyst such as palladium, to obtain a compound of the formula Jack Bernstein and Kathryn Alice Losee, New Brunswick, (In) N.J., assignors to E. R. Squibb & Sons, Inc., New York, 5 Co OH O N.Y., a corporation of Delaware I I No Drawing. Filed June 29, 1967, Ser. No. 649,831

Int. Cl. C07c103/28, 103/46 R1 R1 R US. Cl- 260--518 11 Claims HZN 00 N CH ((I)) N112 R ABSTRACT OF THE DISCLOSURE The compound of Formula III is then iodinated. This This invention relates to new bis-triiodoisophthalamic may be effected by treating the N,N'-alkylenebis(S-aminoacid compounds having the formula isophthalamic acid) of Formula III with an iodinating 1 R R1 R R1 R1 lower A) lower alkanoyl-HN- GO-N- H OHNCO 'NH-alkanoy1 t l l I 1 and to salts and lower alkyl esters of those compounds. 5 agent, e.g., an iodine halide such as iodine chloride, in These compounds are useful as radiopaque agents. aqueous medium in the presence of potassium chloride. This gives a bis-(2,4,6-triiodoisophthalamic acid) of the formula This invention relates to new compounds of Formula I (IV) above and to basic salts of those compounds, e.g., alkali 0001-1 00011 metal salts such as sodium and amine salts such as N- l methylglucamine, as well as lower alkyl esters of the new I- I I( I compounds of Formula I. R1 f f In Formula I, R represents hydrogen, lower alkyl or HQN CONCH(C)nCHNOO NH2 lower alkoxy, n is an integer from 0 to 5 and R reprel h sents hydrogen or lower alkyl. I I

The alkylene chain between the two rings may be straight or branched saturated hydrocarbon chains of 2 o Product of Formula 1S thoh aoylated wlthv an to 7 carbon atoms. There may be one to three lower alkoxy acylahhg hgollt h as n acld anhydrlde or acy l halide, groups on that lower alkylene chain, but not on either 40 acehc ahhydndo acety'l chlorlde, P P h carbon attached to the amide nitrogen. Such lower alkoxy dnde: hhtymyl Chlonde, hexanoyl Chloflde or the like to groups as methoxy, ethoxy, propoxy, butoxy and the like P the final Products of Formulo are illustrative These products form salts with inorganic or organic The lower alkahoyl radicals Which are part of the amide bases, e.g., alkali or alkaline earth metal hydroxides such groups in the 5 pOsitioh of each ring are straight or 4 5 as SOdlllIl'l hydroxide or amines such asN-methylglucamrne branched acyl radicals of the lower fatty acids, e.g., acetyl, or may be converted F estersffi lower alkflholsi by propionyl, butyryl and the like" v treatment of an alkaline solution with a d1(lower alkyl) Preferred are those compounds of Formula I in which f The Salts, especially insoluble Salts, frequently the bridging alkylene chain is an unsubstituted hydrocar- Prowle a Convenient means for isolating and Purifying bon chain of 2 to 3 carbon atoms, especially the former. the P The f r d lower alkanoyl group is acetyL The new products of Formula I are useful as radi- The new compounds f Formula I are produced b opaque agents for v1sualization of animal systems or orforming an N,N alkylenebis(S-nitroisophthalamic acid) galls, Preferably the form of physiologically acceptable dialkyl ester (R =1owe lk l) f h formula salts such as sodium or methylglucamlne salts for the preparation of solutions for intravascular injection for (II) 000% C 0 OR urography and for vasographic techniques such as angiocardiography, arteriography, nephrography and venography. The water-insoluble esters are useful in visualizing l l hollow organs and cavities havin external orifices through which the contrast preparation can be introduced in prep- OzN "cO N OH ((|3)FOHnbFC0 N02 aration for the examination and removal after the exami- R nation is completed. Solutions having about 20 to 50% by the interaction of a 3-carboalkoxy-S-nitrobenzoyl halodmeipreferably about i be used e following examples are illustrative of the invenl1de (preferably the chlonde) and an alkylene diamine AH t t th d 1 such as ethylenediamine, trimethylene diamine, hexamethempera are on 6 can lgra 6 Sea ylenediamine, 2-methoxy-1,4-butanediamine, 1,2-propane- EXAMPLE 1 l i reacnon may be effected m an aqueous (a) Preparation of N,N'-ethylenebis(S-nitroisophthalamic alkaline solution. acid) dimethyl ester The ester of Formula II is then converted to the corresponding free acid (R =H) by treatment with alkali such as sodium carbonate. The two nitro groups are then reduced to amino groups, e.g., catalytically in the presence To a solution of 1.2 grams of ethylene diamine in 50 m1. of acetone there is added a solution of 3.36 grams of sodium bicarbonate in 50 ml. of water. The suspension is cooled to about 5 to and 9.72 grams of 3-carbomethoxy-S-nitrobenzoyl chloride are added, in small portions, with vigorous stirring during thirty minutes. The reaction mixture is allowed to warm to room temperature and is then stirred for an additional four hours. The solid is filtered by suction and washed with water and alcohol to yield N,N'-ethylenebis-(S-nitroisophthalamic acid)dimethyl ester, melting at about 252-255 after crystallization from aqueous dimethylformamide.

(b) N,N'-ethylenebis(S-nitroisophthalamic acid) To a suspension of 2.37 grams of N,N-ethylenebis(- nitroisophthalamic acid dimethyl ester in a mixture of 60 ml. of acetone and 60 ml. of water there are added 1.06 grams of sodium carbonate. The mixture is stirred at room temperature for one hour and then heated on a steam bath for 2 /2 hours. The clear solution is then concentrated under reduced pressure to remove the acetone and the aqueous solution is treated with decolorizing carbon. The solution is filtered and the filtrate is made strongly acid with hydrochloric acid. The precipitated solid is filtered and washed with water to yield N,N-ethylenebis(5-nitroisophthalarnic acid). The acid, which does not melt below 300, is crystallized from aqueous dimethylformamide.

(c) N,N'-ethylenebis(S-aminoisophthalamic acid) To a solution of 4.46 grams of N,N-ethylenebis(5- nitroisophthalamic acid) in 20 ml. of N-NaOH solution there are added 75 ml. of water and 500 mg. of 5% palladium on charcoal catalyst. The mixture is shaken at room temperature at 50 p.s.i. of hydrogen until the absorption of hydrogen is complete. The catalyst is removed by filtration and the aqueous filtrate acidified with acetic acid. The precipitated solid is filtered and washed with water to yield N,N-ethylenebis(S-aminoisophthalamic acid) as a white solid which does not melt below 300.

(d) N,N-ethylenebis(5-amino-2,4,6-triiodoisophthalamic acid) To a suspension of 7.72 grams of N,N-ethylenebis- (S-aminoisophthalamic acid) in 100 ml. of Water there is added, dropwise, during minutes, a solution of 16 grams of ICl and 12.4 grams of KCl in 70 ml. of Water. The mixture is stirred at room temperature for three hours and ml. of N-NaOI-I solution and a solution of 8 grams of 1G1 and 6.2 grams of KCl in 40 ml. of water are added. The reaction mixture is stirred overnight. The solid is filtered and dissolved in 500 ml. of water and ml. of

N-NaOH solution. To this solution are added 20 grams of sodium bisulfite and the resulting solution is allowed to remain at room temperature overnight. The solution is treated with decolorizing carbon, filtered and acidified. The precipitated solid is filtered and washed thoroughly with water to yield N,N-ethylenebis(5-amino-2,4,6-triiodoisophthalamic acid) which does not melt below 300.

(e) N,N-ethylenebis(S-acetamido-2,4,6-triiodoisophthalamic acid) A mixture of 5.5 grams of N,N-ethylenebis(S-arnino- 2,4,6-triiodoisophthalamic acid) and ml. of acetic anhydride containing 2 drops of concentrated sulfuric acid is refluxed with stirring for about two hours. The cooled reaction mixture is filtered, concentrated under reduced pressure to remove the excess acetic anhydride and poured into ice water. The precipitated solid is filtered and washed thoroughly with water. The solid is dissolved in ethanol, treated with decolorizing carbon, filtered and the filtrate concentrated to dryness. The N,N'-ethylenebis-(S-acetamide-2,4,6-triiodoisophthalamic acid) thus obtained does not melt below 300.

EXAMPLE 2 Following the procedure of Example 1, but substituting an equivalent amount of N,N-dimethylethylenediamine 4 for the ethylenediamine there is obtained the desired N,N- dimethyl-N,N'-ethylenebis(5-acetan1ide-2,4,6 triiodoisophthalamic acid).

EXAMPLE 3 Following the procedure of Example 1, but substituting an equivalent amount of 1,2-propanediamine for the ethylene diamine there is obtained the desired N,N-1,2-propylenebis(S-acetamido-Z,4,6-triiodoisophthalamic acid).

EXAMPLE 4 Following the procedure of Example 1, but substituting an equivalent amount of butyric anhydride for the acetic anhydride there is obtained the desired N,N'-ethylenebis- (5-butyramido-2,4,6-triiodoisophthalamic acid).

EXAMPLE 5 Following the procedure of Example 1, but substituting an equivalent amount of 2,3-dimethoxy-1,4-butanediamine for the ethylenediamine there is obtained the desired N,N- (2,3-dimethoxytetramethylene)bis(5-acetamido 2,4,6-triiodoisophthalamic acid).

EXAMPLE 6 Following the procedure of Example 1, but substituting an equivalent amount of 2-methoxy-1,4-butanediamine for the ethylenediamine there is obtained the desired N,N'-(2- methoxytetramethylene)bis(5-acetamido-2,4,6 triiodoisophthalamic acid).

EXAMPLE 7 Following the procedure of Example 1, but substituting an equivalent amount of 3-methoxy-1,6-hexanediamine for the ethylenediamine, there is obtained the desired N,N'- t3-methoxyhexamethylene)bis(acetamido-2,4,6 triiodo isophthalamic acid).

EXAMPLE 8 Following the procedure of Example 1, but substituting an equivalent amount of 2,2-dimethyl-l,3-propanediamine for the ethylenediamine there is obtained the desired N,N-(2,2-dimethyltrimethylene)bis(5 acetamido 2,4,6- triiodoisophthalamic acid).

EXAMPLE 9 Following the procedure of Example 1, but substituting an equivalent amount of N,N'-isopropyl-1,6-hexanediamine for the ethylenediamine there is obtained the desired N,N-diisopropyl-N,N' hexamethylenebis(5 acetamido-2,4,6-triiodoisophthalamic acid).

EXAMPLE 10 Following the procedure of Example 1, but substituting an equivalent amount of 3-isobutoxy-1,6-hexanediamine for the ethylenediamine there is obtained the desired N,N (3 isobutoxy hexamethylene)bis(5 acetamido- 2,4,6-triiodoisophthalamic acid).

EXAMPLE 11 A solution of 6.6 grams of potassium hydroxide in 200 ml. of ethanol is added to a suspension of 61 grams of N,N' ethylenebis(5 acetamido 2,4,6 triiodoisophthalamic acid) in 500 ml. of ethanol. To this mixture there is then added slowly, with vigorous stirring 12.6 grams of dimethyl sulfate and the mixture stirred for six hours. The reaction mixture is diluted with 1 liter of water and the solid removed by filtration. The dimethyl ester of N,N'-ethy1enebis(S-acetamido 2,4,6 triiodoisophthalamic acid) thus obtained is further purified by dissolving the solid in hot dimethylformamide, filtering and diluting the filtrate with water. The product is collected by filtration and washed thoroughly with water.

EXAMPLE 12 Following the procedure of Example 11, but substituting an equivalent amount of diethyl sulfate for the dimethyl sulfate there is obtained the desired diethyl diester of N,N-ethylenebis(S-acetamido 2,4,6 triiodowherein R is hydrogen, lower alkyl or lower alkoxy,

isophthalamic acid). R is hydrogen or lower alkyl and n is to 5,

EXAMPLE 13 and lower alkyl esters and physiologically acceptable salts To a stirred mixture of 28.5 grams of N,N'-ethylenebisthereof. (-amino-2,4,6-triiodoisophthalamic acid) in 500 ml. of 5 2. A compound as in claim 1 wherein each R and R dimethylacetamide there is added 25 grams of n-hexanoyl is hydrogen and n is 0. chloride and the mixture heated with stirring at 100 for 3. A compound as in claim 2 wherein the lower four hours and then poured into water and allowed to alkanoyl group is acetyl.

stir at room temperature for twenty-four hours. The 4. A compound as in claim 1 wherein the R on each precipitated solid is dissolved in dilute sodium hydroxide, 1O nitrogen is lower alkyl and each other R and R are treated with decolorizing carbon and then acidified with hydrogen, and nis 0. dilute hydrochloric acid. The N,N'-ethylenebis(S-n-hex- 5. A compound as in claim 4 wherein the lower anoylamido-2,4,6 triiodoisophthalamic acid) is filtered alkyl group is methyl and the lower alkanoyl group is and washed thoroughly with water. acetyl.

EXAMPLE 14 6. A compound as in claim 1 wherein each R and each R on the nitrogen is hydrogen, each R on the carbon To a suspension of 122.6 grams of N,N'-ethyleneb1s(5- is lower alkyl and n is acetamido-Z,4,6-triiodoisophthalamic acid) in 1 liter of A compound as in claim 6 wherein the lower alkyl Water there is added 200 ml. of N-sodium hydroxide solugroup is methyL tion and the resulting solution lyophilized to yield the 8. A compound as in claim 1 wherein each R and R1 desired disodium salt of N,N-ethylenebis(S-acetamidois hydrogen, n is 1 and each lower alkanoyl group is 2,4,6-triiodoisophthalamic acid). acetyL Similarly, by using an equivalent amount of N-methyl- A compound of the formula glucamine there is obtained the desired N-methylglucamine salt of N,N'-ethylenebis(5-acetamido-2,4,6-triiodoisophthalamic acid).

EXAMPLE 15 000E COOH A solution suitable for use in intravenous urography 3O has the following composition (per 100 ml.): 1 N,N-ethylenebis(S-acetamido-2,4,6-triiod0iso- R R1 R1 phthalamic acid, sodium salt63.5 grams HZN Sodium citrate (as buifer)320 mg. l Disodium ethylenediamine tetraacetic acid I I dihydrate (sequestering agent)40 mg. Methyl paraben (as preservative)- mg. Propyl paraben (as preservative)--30 mg.

The solution is prepared by dissolving the sodium salt 40 wherein R, R and n have the same meaning as in in a limited amount of sterile water, adjusting the pH to claim 1. about 7, adding the rest of the components and adjusting 10. A compound as in claim 9 wherem each R and R the final volume to 100 ml. is hydrogen and n is 0.

What is claimed is: 11. A compound as in claim 9 wherein each R and R 1. A compound of the formula is hydrogen and n is 1.

R1 R1 R R1 R1 1 lower I (l: A} I lower alkanoyl-EN O O--N- H-- (1 H-NCO NH-alkanoyl References Cited UNITED STATES PATENTS 3,178,473 4/1965 Holtermann et al. 260519 3,306,927 2/1967 Larsen 260-518 3,409,662 11/1968 Larsen 260518 LORRAINE A. WEINBERGER, Primary Examiner L. A. THAXTON, Assistant Examiner US. Cl. X.R. 

